System and process for treatment of myopia

ABSTRACT

A process for preventing or treating myopia includes applying a pulsed energy, such as a pulsed laser beam, to tissue of an eye having myopia or a risk of having myopia. The source of pulsed energy has energy parameters including wavelength or frequency, duty cycle and pulse train duration, which are selected so as to raise an eye tissue temperature up to eleven degrees Celsius to achieve therapeutic or prophylactic effect, such as stimulating heat shock protein activation in the eye tissue. The average temperature rise of the eye tissue over several minutes is maintained at or below a predetermined level so as not to permanently damage the eye tissue.

RELATED APPLICATIONS

This application is a continuation of co-pending U.S. application Ser.No. 15/813,645, filed on Nov. 15, 2017, which is a divisional of U.S.patent application Ser. No. 15/629,002, filed Jun. 21, 2017, which is acontinuation-in-part of U.S. application Ser. No. 15/583,096 filed May1, 2017, which is a continuation-in-part of U.S. application Ser. No.15/214,726 filed on Jul. 20, 2016, which is a continuation-in-part ofU.S. application Ser. No. 14/922,885 filed on Oct. 26, 2015 (now U.S.Pat. No. 9,427,602) (which claims priority from U.S. ProvisionalApplication No. 62/153,616 filed on Apr. 28, 2015), which is acontinuation-in-part of U.S. application Ser. No. 14/607,959 filed onJan. 28, 2015 (now U.S. Pat. No. 9,168,174), which is acontinuation-in-part of U.S. application Ser. No. 13/798,523 filed onMar. 13, 2013, which is a continuation-in-part of U.S. application Ser.No. 13/481,124 filed on May 25, 2012 (now U.S. Pat. No. 9,381,115), andis also a continuation-in-part of U.S. application Ser. No. 15/232,320filed on Aug. 9, 2016, which is a continuation-in-part of U.S.application Ser. No. 15/188,608 filed Jun. 21, 2016, which is acontinuation-in-part of U.S. application Ser. No. 15/148,842 filed onMay 6, 2016, which is a continuation-in-part of U.S. application Ser.No. 14/921,890 filed Oct. 23, 2015 (now U.S. Pat. No. 9,381,116), whichis a continuation-in-part of U.S. application Ser. No. 14/607,959 filedJan. 28, 2015 (now U.S. Pat. No. 9,168,174). This application is also acontinuation-in-part of U.S. application Ser. No. 15/460,821 filed Mar.16, 2017, which is a continuation-in-part of U.S. application Ser. No.15/214,726, filed Jul. 20, 2016, which is a continuation-in-part of U.S.application Ser. No. 14/922,885, filed on Oct. 26, 2015, now U.S. Pat.No. 9,427,602 (which claims the benefit of U.S. Application No.62/153,616, filed on Apr. 28, 2015), which is a continuation-in-part ofU.S. application Ser. No. 14/607,959 filed on Jan. 28, 2015, now U.S.Pat. No. 9,168,174, which is a continuation-in-part of U.S. applicationSer. No. 13/798,523, filed on Mar. 13, 2013, which is acontinuation-in-part of U.S. application Ser. No. 13/481,124, filed onMay 25, 2012, now U.S. Pat. No. 9,381,115, and is also acontinuation-in-part of U.S. application Ser. No. 15/148,842, filed May6, 2016, which is a continuation-in-part of U.S. application Ser. No.14/921,890, filed Oct. 23, 2015, now U.S. Pat. No. 9,381,116, which is acontinuation-in-part of U.S. application Ser. No. 14/607,959, filed onJan. 28, 2015, now U.S. Pat. No. 9,168,174, which is acontinuation-in-part of U.S. application Ser. No. 13/798,523, filed Mar.13, 2013, which is a continuation-in-part of U.S. application Ser. No.13/481,124, filed on May 25, 2012, now U.S. Pat. No. 9,381,115; and alsoa continuation-in-part of U.S. application Ser. No. 15/075,432, filed onMar. 21, 2016, which is a continuation of U.S. application Ser. No.13/798,523, filed on Mar. 13, 2013, which is a continuation-in-part ofU.S. application Ser. No. 13/481,124, filed May 25, 2012, now U.S. Pat.No. 9,381,115. This application is also a continuation-in-part of U.S.application Ser. No. 15/332,132 filed Oct. 24, 2016, which is adivisional of U.S. application Ser. No. 15/232,320, filed Aug. 9, 2016,which is a continuation-in-part of U.S. application Ser. No. 15/148,842,filed May 6, 2016 which is a continuation-in-part of U.S. applicationSer. No. 14/921,890, filed Oct. 23, 2015 (now U.S. Pat. No. 9,381,116),which is a continuation-in-part of U.S. application Ser. No. 14/607,959,filed Jan. 28, 2015 (now U.S. Pat. No. 9,168,174), which is acontinuation-in-part of U.S. application Ser. No. 13/798,523, filed Mar.13, 2013, which is a continuation-in-part of U.S. application Ser. No.13/481,124, filed May 25, 2012 (now U.S. Pat. No. 9,381,115); and isalso a continuation-in-part of U.S. application Ser. No. 15/188,608,filed Jun. 21, 2016, which is a continuation of U.S. application Ser.No. 13/481,124, filed May 25, 2012 (now U.S. Pat. No. 9,381,115); and isa continuation-in-part of U.S. application Ser. No. 13/798,523, filedMar. 13, 2013, which is a continuation-in-part of U.S. application Ser.No. 13/481,124, filed May 25, 2012 (now U.S. Pat. No. 9,381,115). Thisapplication is also a continuation-in-part of U.S. application Ser. No.15/291,796 filed Oct. 12, 2016 which is a divisional of U.S. Ser. No.15/148,842, filed May 6, 2016, which is a continuation-in-part of U.S.application Ser. No. 14/921,890, filed Oct. 23, 2015, which is acontinuation-in-part of U.S. application Ser. No. 14/607,959, filed Jan.28, 2015 (now U.S. Pat. No. 9,168,174), which is a continuation-in-partof U.S. application Ser. No. 13/798,523, filed Mar. 13, 2013, which is acontinuation-in-part of U.S. application Ser. No. 13/481,124, filed May25, 2012; and is also a continuation-in-part of U.S. application Ser.No. 15/075,432, filed Mar. 21, 2016, which is a continuation of U.S.application Ser. No. 13/798,523, filed Mar. 13, 2013, which is acontinuation-in-part of U.S. application Ser. No. 13/481,124, filed May25, 2012. This application is also a continuation-in-part of U.S.application Ser. No. 15/232,320 filed Aug. 9, 2016 which is acontinuation-in-part of U.S. application Ser. No. 15/148,842, filed May6, 2016 which is a continuation-in-part of U.S. application Ser. No.14/921,890, filed Oct. 23, 2015 (now U.S. Pat. No. 9,381,116), which isa continuation-in-part of U.S. application Ser. No. 14/607,959, filedJan. 28, 2015 (now U.S. Pat. No. 9,168,174), which is acontinuation-in-part of U.S. application Ser. No. 13/798,523, filed Mar.13, 2013, which is a continuation-in-part of U.S. application Ser. No.13/481,124, filed May 25, 2012 (now U.S. Pat. No. 9,381,115); and isalso a continuation-in-part of U.S. application Ser. No. 15/188,608,filed Jun. 21, 2016, which is a continuation of U.S. application Ser.No. 13/481,124, filed May 25, 2012 (now U.S. Pat. No. 9,381,115); and isa continuation-in-part of U.S. application Ser. No. 13/798,523, filedMar. 13, 2013, which is a continuation-in-part of U.S. application Ser.No. 13/481,124, filed May 25, 2012 (now U.S. Pat. No. 9,381,115). Thisapplication is also a continuation-in-part of U.S. application Ser. No.15/214,726 filed Jul. 20, 2016 which is a continuation-in-part of U.S.application Ser. No. 14/922,885, filed on Oct. 26, 2015 (which claimsthe benefit of U.S. Application No. 62/153,616, filed on Apr. 28, 2015),which is a continuation-in-part of U.S. application Ser. No. 14/607,959filed on Jan. 28, 2015, now U.S. Pat. No. 9,168,174, which is acontinuation-in-part of U.S. application Ser. No. 13/798,523, filed onMar. 13, 2013, which is a continuation-in-part of U.S. application Ser.No. 13/481,124, filed on May 25, 2012, now U.S. Pat. No. 9,381,115. Thisapplication is also a continuation-in-part of U.S. application Ser. No.15/188,608 filed Jun. 21, 2016 which is a continuation of U.S.application Ser. No. 13/481,124 filed May 25, 2012. This application isalso a continuation-in-part of U.S. application Ser. No. 15/148,842filed May 6, 2016 which is a continuation-in-part of U.S. applicationSer. No. 14/921,890, filed Oct. 23, 2015, which is acontinuation-in-part of U.S. application Ser. No. 14/607,959, filed Jan.28, 2015 (now U.S. Pat. No. 9,168,174), which is a continuation-in-partof U.S. application Ser. No. 13/798,523, filed Mar. 13, 2013, which is acontinuation-in-part of U.S. application Ser. No. 13/481,124, filed May25, 2012; and is also a continuation-in-part of U.S. application Ser.No. 15/075,432, filed Mar. 21, 2016, which is a continuation of U.S.application Ser. No. 13/798,523, filed Mar. 13, 2013, which is acontinuation-in-part of U.S. application Ser. No. 13/481,124, filed May25, 2012. This application is also a continuation-in-part of U.S.application Ser. No. 15/075,432 filed Mar. 21, 2016 which is acontinuation of U.S. application Ser. No. 13/798,523, filed Mar. 13,2013, which is a Continuation-in-Part of U.S. application Ser. No.13/481,124, filed May 25, 2012.

BACKGROUND OF THE INVENTION

The present invention generally relates to systems and processes fortreating eye disorders. More particularly, the present invention residesin systems and processes for preventing or treating myopia by applyingpulsed energy to tissue of an eye having myopia or a risk of havingmyopia to raise the temperature of the eye tissue sufficiently toprovide treatment benefits while not permanently damaging the eyetissue.

Myopia is the condition known as “near-sightedness”, where the image infront of the eye is focused in front of the retina rather than exactlyon the retina. This focus of the image on the retina is also referred toas “emmetropia”. The image in myopia may be focused in front of theretina for one or both of the following reasons: either the refractivestrength of the front of the eye at the cornea and lens is excessive;and/or the axial length of the eye is too long, such that the retina isposterior to the image focal point, causing blurred vision. Tocounteract this visual blurring, those affected move closer to theobject to be viewed. This moves the focal point of the image back andcloser to the retina, causing the vision to become more clear.

Myopia is epidemic by usual medical definitions, affecting as many as50% of adults, with increases in incidents in school-aged children inrecent generations by 200% or more. This rapid increase and prevalencehas been attributed to improved educational opportunities with increasedreading time, as well as increased use of electronic devices and media.

The causes of typical myopia appear to be genetic and environment.Higher education and greater time spent doing close work and reading areknown to be risk factors for myopia. The stimulus for near work causingmyopia suggests that this influences, possibly in part via accommodationof the crystalline lens, neurologic and/or chemical mediators of eyegrowth to increase the axial length of the eye. Evidence for thisphenomenon is that paralyzation of accommodation with topical atropinein children is able to reduce the degree and incidence of acquiredmyopia.

The “emmetropic” factor or factors that promote normal eye growth andformation and axial length and that are diminished, blocked or inhibitedby near work lead to an increase in eye length, most likely arise in thecentral retina or “macula” where visual images are normally focused. Byhard-wired neurologic and/or diffusible chemical feedback mechanisms,auto regulation of ocular growth is disturbed to adapt the eye to themyopic focal point by encouraging actively, or allowing passively byloss of emmetropic stimulus, an increase in the axial length of the eye,increasing the condition of myopia.

Retinal dysfunction and alteration of retinal autoregulation in responseto environmental factors is a common phenomenon and a common finding inmost chronic progressive retinopathies, including age-related maculardegeneration and diabetic retinopathy, ocular neurologic diseases suchas chronic open angle glaucoma, and inherited retinopathies includingretinitis pigmentosa and Stargardt's Disease. In glaucoma a settinganalogous to the development of myopia, selective complimentary sparingof visual field defects has demonstrated direct and neurologic and/orchemical communication between fellow eyes mediated by the centralnervous system to minimize total visual disability. In response to higheye pressure in glaucoma, optic nerve tissue is sacrificed in such a wayas to increase the probability of preserved visual field in one eye,covering lost visual field in the other eye, maximizing total visualfunction when both eyes are used together. Thus, there is a clearanatomic response mediated by retinal signaling which alters retinal andneurologic structure to accommodate the quality of visual stimuli andmaximize visual function.

Pediatric myopic appears to develop and progress in the same manner andby similar mechanisms as other chronic progressive ocular diseases. Anabnormal stimulus (chronic near-work and lens accommodation) causingalteration of retinal function and autoregulation in response to theabnormal environment, thus becomes abnormal and causes elongative growthto the eye to restore sharp near vision with less accommodative effort,and thus the condition of myopia develops.

While typical axial or refractive myopia can be corrected by glasses,contact lenses or refractive surgery, myopia is also often associatedwith reduced visual function and increases risks of vision loss due toretinal detachment, choroidal neovascularization, macular atrophy, andglaucoma. Together, the need for refractive correction of myopia, andmedical consequences, constitute a significant public health problem andsocioeconomic burden.

Accordingly, there is a continuing need for systems and methods whichcan prevent and/or treat the eye condition of myopia. Such a system ormethod should be able to modify biological factors that may contributeto acquired myopia, so as to slow or prevent acquired myopia. Such asystem and method of treatment should be relatively easy to perform andharmless. The present invention fulfills these needs, and provides otherrelated advantages.

SUMMARY OF THE INVENTION

The present invention resides in a process for preventing or treatingmyopia. A pulsed energy source having energy parameters, includingwavelength or frequency, duty cycle and pulse duration is provided. Theenergy parameters are selected so as to raise an eye tissue temperatureup to 11° C. to achieve a therapeutic or prophylactic effect. Theaverage temperature rise of the eye tissue over several minutes ismaintained at or below a predetermined level so as not to permanentlydamage the eye tissue. It may be determined that the eye has myopia oris at a risk of having myopia. The pulsed energy is applied to tissue ofan eye having a myopia or a risk of having myopia to stimulate heatshock protein activation in the eye tissue.

The pulsed energy may comprise a pulsed light beam having a wavelengthbetween 530 nm to 1300 nm, and more particularly between 80 nm and 1000nm. The light beam may have a duty cycle of less than 10%, and morepreferably between 2.0% and 5%. The pulsed light beam may have a powerbetween 0.5 and 74 watts. The pulsed light beam may have a pulse trainduration between 0.1 and 0.6 seconds.

Typically, the eye tissue to which the pulsed energy is appliedcomprises retinal and/or foveal tissue. The pulsed energy source energyparameters are selected so that the eye tissue temperature is raisedbetween 6° C. to 11° C. at least during application of the pulsed energysource. However, the average temperature rise of the eye tissue ismaintained at approximately 1° C. or less over several minutes, such asover a six-minute period of time.

The pulsed energy may be applied to a plurality of eye tissue areas,wherein adjacent eye tissue areas are separated by at least apredetermined distance to avoid thermal tissue damage. The pulsed energymay be applied to a first eye tissue area and, after a predeterminedperiod of time within a single treatment session, the pulsed energy isreapplied to the first eye tissue area. During an interval betweenpulsed energy applications to the first eye tissue area, the pulsedenergy is applied to a second eye tissue area.

Other features and advantages of the present invention will becomeapparent from the following more detailed description, taken inconjunction with the accompanying drawings, which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate the invention. In such drawings:

FIG. 1 is a graph illustrating an average power of a laser source havinga wavelength compared to a source radius and pulse train duration of thelaser;

FIG. 2 is a graph similar to FIG. 1, illustrating the average power of alaser source of a higher wavelength compared to a source radius and apulse train duration of the laser;

FIG. 3 is a diagrammatic view illustrating a system used for treating aneye in accordance with the present invention;

FIG. 4 is a diagrammatic view of an exemplary optical lens or mask usedto generate a geometric pattern, in accordance with the presentinvention;

FIG. 5 is a diagrammatic view illustrating an alternate embodiment of asystem used for treating eye tissue in accordance with the presentinvention;

FIG. 6 is a diagrammatic view illustrating yet another alternateembodiment of a system used for treating eye tissue in accordance withthe present invention;

FIG. 7 is a front view of a camera including an iris aperture of thepresent invention;

FIG. 8 is a front view of a camera including an LCD aperture, inaccordance with the present invention;

FIG. 9 is a top view of an optical scanning mechanism, used inaccordance with the present invention;

FIG. 10 is a partially exploded view of the optical scanning mechanismof FIG. 9, illustrating various component parts thereof;

FIG. 11 is a diagrammatic view illustrating controlled offset ofexposure of an exemplary geometric pattern grid of laser spots to treatthe eye tissue, in accordance with the present invention;

FIG. 12 is a diagrammatic view illustrating units of a geometric objectin the form of a line controllably scanned to treat an area of eyetissue, in accordance with the present invention;

FIG. 13 is a diagrammatic view similar to FIG. 12, but illustrating thegeometric line or bar rotated to treat an area of the retina, inaccordance with the present invention;

FIGS. 14A-FIG. 14D are diagrammatic views illustrating the applicationof laser light to different treatment areas during a predeterminedinterval of time, within a single treatment session, and reapplying thelaser light to previously treated areas, in accordance with the presentinvention; and

FIGS. 15-17 are graphs depicting the relationship of treatment power andtime in accordance with embodiments of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As shown in the accompanying drawings, and as more fully describedherein, the present invention is directed to a process for preventing ortreating myopia. This is accomplished by providing a pulsed energysource having energy parameters selected so as to raise an eye tissuetemperature sufficiently to achieve a therapeutic or prophylacticeffect, while maintaining the average temperature rise of the eye tissueover time at or below a predetermined level so as not to permanentlydamage the eye tissue.

As indicated above, the prevalence myopia has increased dramaticallyworldwide within the last few decades. Recent studies have shown thatrefractive development or myopia is influenced by environmental,behavioral and inherited factors. The inventors believe that there aremodifiable biologic factors behind the development of simple, acquiredmyopia. Low-intensity and high-density subthreshold diode micropulsedlaser (SDM) has been demonstrated by the inventors to improve thephysiologic and psychophysical function of the eye and optic nerve in amyriad of chronic progressive retinal diseases and open angle glaucoma.Research has indicated that SDM does this by normalizing retinalfunction and autoregulation by a mechanism referred to by the inventorsas “reset to default” effect or homeotrophy. By selectively targetingand normalizing the function of the retinal pigment epithelium (RPE),which is the main driver for retinal function and autoregulation, thebiologic function of the RPE, if made abnormal due to environmental orother causes, is reset to default, or returned to normal function. By sodoing, the progression of the disease is slowed, stopped or evenreversed. The inventors believe that SDM homeotropic therapy, byrestoring normal retinal physiology and autoregulation should then slow,stop or even reverse progression of myopia, and particularly pediatricmyopia, in the same way that it does other chronic progressiveretinopathies and glaucoma. Clinical experience and use in other oculardisorders including diabetic retinopathy, age-related maculardegeneration, glaucoma, and inherited retinopathies, suggest that theeffective SDM homeotrophic therapy should be both robust and renewableby periodically repeated treatments.

The inventors have discovered that electromagnetic radiation, such as inthe form of various wavelengths of laser light, can be applied toretinal tissue in a manner that does not destroy or damage the tissuewhile achieving beneficial effects on eye diseases. It is believed thatthis may be due, at least in part, to the stimulation and activation ofheat shock proteins and the facilitation of protein repair in thetissue. It is believed that the creation of a thermal time-coursestimulates heat shock protein activation or production and facilitatesprotein repair without causing any damage.

The inventors have found that a laser light beam can be generated thatis therapeutic, yet sublethal to retinal tissue cells and thus avoidsdamaging photocoagulation in the retinal tissue which providespreventative and protective treatment of the retinal tissue of the eye.Various parameters of the light beam must be taken into account andselected so that the combination of the selected parameters achieve thetherapeutic effect while not permanently damaging the tissue. Theseparameters include laser wavelength, radius of the laser source, averagelaser power, total pulse duration, and duty cycle of the pulse train.Although a laser light beam is used in a particularly preferredembodiment, other pulsed energy sources including ultrasound,ultraviolet frequency, microwave frequency and the like having energyparameters appropriately selected may also be used, but are not asconvenient in the treatment of eye disorders and diseases, includingmyopia, as other diseases and disorders.

The selection of these parameters may be determined by requiring thatthe Arrhenius integral for HSP activation be greater than 1 or unity.Arrhenius integrals are used for analyzing the impacts of actions onbiological tissue. See, for instance, The CRC Handbook of ThermalEngineering, ed. Frank Kreith, Springer Science and Business Media(2000). At the same time, the selected parameters must not permanentlydamage the tissue. Thus, the Arrhenius integral for damage may also beused, wherein the solved Arrhenius integral is less than 1 or unity.

Alternatively, the FDA/FCC constraints on energy deposition per unitgram of tissue and temperature rise as measured over periods of minutesbe satisfied so as to avoid permanent tissue damage. The FDA/FCCrequirements on energy deposition and temperature rise are widely usedand can be referenced, for example, at

www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm073817.htm#attacha for electromagnetic sources, and Anastosio andP. LaRivero, ed., Emerging Imaging Technologies. CRC Press (2012), forultrasound sources.

Generally speaking, tissue temperature rises of between 6° C. and 11° C.can create therapeutic effect, such as by activating heat shockproteins, while maintaining the average tissue temperature over aprolonged period of time, such as over several minutes, such as sixminutes, below a predetermined temperature, such as 6° C. and even 1° C.or less in certain circumstances, will not permanently damage thetissue.

The subthreshold retinal photocoagulation, sometimes referred to as“true subthreshold”, of the invention is defined as retinal laserapplications biomicroscopically invisible at the time of treatment.“True subthreshold” photocoagulation, as a result of the presentinvention, is invisible and includes laser treatment non-discernible byany other known means such as FFA, FAF, or even SD-OCT. “Truesubthreshold” photocoagulation is therefore defined as a laser treatmentwhich produces absolutely no retinal damage detectable by any means atthe time of treatment or any time thereafter by known means ofdetection. As such, “true subthreshold” is the absence of lesions andother tissue damage and destruction. The invention may be moreaccurately referred to as photostimulation than photocoagulation due tothe absence of typical photocoagulation damage.

Various parameters have been determined to achieve “true subthreshold”or “low-intensity” effective photocoagulation. These include providingsufficient power to produce effective treatment retinal laser exposure,but not too high to create tissue damage or destruction. Truesubthreshold laser applications can be applied singly or to create ageometric object or pattern of any size and configuration to minimizeheat accumulation, but assure uniform heat distribution as well asmaximizing heat dissipation such as by using a low duty cycle. Theinventor has discovered how to achieve therapeutically effective andharmless true subthreshold retinal laser treatment. The inventor hasalso discovered that placement of true subthreshold laser applicationsconfluently and contiguously to the retinal surface improves andmaximizes the therapeutic benefits of treatment without harm or retinaldamage.

It has been found that the intensity or power of a low-duty cycle 810 nmlaser beam between 100 watts to 590 watts per square centimeter iseffective yet safe. A particularly preferred intensity or power of thelaser light beam is approximately 250-350 watts per square centimeterfor an 810 nm micropulsed diode laser.

Power limitations in current micropulsed diode lasers require fairlylong exposure duration. The longer the laser exposure, the moreimportant the center-spot heat dissipating ability toward the unexposedtissue at the margins of the laser spot and toward the underlyingchoriocapillaris. Thus, the radiant beam of an 810 nm diode laser shouldhave an exposure envelope duration of 500 milliseconds or less, andpreferably approximately 100-300 milliseconds. Of course, if micropulseddiode lasers become more powerful, the exposure duration will belessened accordingly. It will be understood that the exposure envelopeduration is a duration of time where the micropulsed laser beam would beexposed to the same spot or location of the retina, although the actualtime of exposure of the tissue to the laser is much less as the laserlight pulse is less than a millisecond in duration, and typicallybetween 50 microseconds to 100 microseconds in duration.

Invisible phototherapy or true subthreshold photocoagulation inaccordance with the present invention can be performed at various laserlight wavelengths, such as from a range of 532 nm to 1300 nm. Use of adifferent wavelength can impact the preferred intensity or power of thelaser light beam and the exposure envelope duration in order that theretinal tissue is not damaged, yet therapeutic effect is achieved.

Another parameter of the present invention is the duty cycle (thefrequency of the train of micropulses, or the length of the thermalrelaxation time in between consecutive pulses). It has been found thatthe use of a 10% duty cycle or higher adjusted to deliver micropulsedlaser at similar irradiance at similar MPE levels significantly increasethe risk of lethal cell injury, particularly in darker fundi. However,duty cycles less than 10%, and preferably approximately 5% duty cycle orless have demonstrated adequate thermal rise and treatment at the levelof the RPE cell to stimulate a biologic response, but remained below thelevel expected to produce lethal cell injury, even in darkly pigmentedfundi. Moreover, if the duty cycle is less than 5%, the exposureenvelope duration in some instances can exceed 500 milliseconds.

In a particularly preferred embodiment, the use of small retinal laserspots is used. This is due to the fact that larger spots can contributeto uneven heat distribution and insufficient heat dissipation within thelarge retinal laser spot, potentially causing tissue damage or eventissue destruction towards the center of the larger laser spot. In thisusage, “small” would generally apply to retinal spots less than 3 mm indiameter. However, the smaller the retinal spot, the more ideal the heatdissipation and uniform energy application becomes. Thus, at the powerintensity and exposure duration described above, small spots, such as25-300 micrometers in diameter, or small geometric lines or otherobjects are preferred so as to maximize even heat distribution and heatdissipation to avoid tissue damage.

Thus, the following key parameters have been found in order to createharmless, “true subthreshold”, sublethal micropulsed laser light beam toachieve the aims of the present invention, including wavelength orfrequency, duty cycle and pulse duration. The laser light beam shouldhave a wavelength greater than 532 nm to avoid cytotoxic photochemicaleffects, such as a wavelength between 550 nm and 1300 nm, and in aparticularly preferred embodiment between 810 nm and 1000 nm. The dutycycle should be less than 10%, and preferably between 2.5%-5%. The pulsetrain duration or exposure time should be between 100 and 600milliseconds. The intensity or power of the laser light beam should bebetween 100-590 watts per square centimeter at the retina orapproximately 1 watt per laser spot for each treatment spot at theretina. This is sufficient power to produce retinal laser exposuresbetween 18-55 times Maximum Permissible Exposure (MPE) and retinalirradiance of between 100-590 W/cm². Preferably, small spot size is usedto minimize heat accumulation and assure uniform heat distributionwithin a given laser spot so as to maximize heat dissipation.

Using the foregoing parameters, a harmless yet therapeutically effective“true subthreshold” or invisible phototherapy treatment can be attainedin which retinal photostimulation of all areas of the RPE may be exposedto the laser radiation and preserved and available to contributetherapeutically. The present invention has been found to produce thebenefits of conventional photocoagulation and phototherapy whileavoiding the drawbacks and complications of conventional phototherapy.In accordance with the present invention, the physician may apply thelaser light beam to treat the entire retina, including sensitive areassuch as the macula and even the fovea, without creating visual loss orother damage. This is not possible using conventional phototherapies asit could create damage to the eye or even blindness.

It is conventional thinking that tissue damage and lesions must becreated in order to have a therapeutic effect. However, the inventorshave found that this simply is not the case. In the absence oflaser-induced retinal damage, there is no loss of functional retinaltissue and no inflammatory response to treatment. Adverse treatmenteffects are thus completely eliminated and functional retina preservedrather than sacrificed. This may yield superior visual acuity resultscompared to conventional photocoagulation treatment.

The present invention spares the neurosensory retina and is selectivelyabsorbed by the RPE. Current theories of the pathogenesis of retinalvascular disease especially implicate cytokines, potent extra cellularvasoactive factors produced by the RPE, as important mediators ofretinal vascular disease. The present invention both selectively targetsand avoids lethal buildup within RPE. Thus, with the present inventionthe capacity for the treated RPE to participate in a therapeuticresponse is preserved and even enhanced rather than eliminated as aresult their destruction of the RPE in conventional photocoagulationtherapies.

It has been noted that the clinical effects of cytokines may follow a“U-shaped curve” where small physiologic changes in cytokine production,denoted by the left side of curve, may have large clinical effectscomparable to high-dose (pharmacologic) therapy (denoted by the rightside of the curve). Using sublethal laser exposures in accordance withthe present invention may be working on the left side of the curve wherethe treatment response may approximate more of an “on/off” phenomenonrather than a dose-response. This might explain the clinicaleffectiveness of the present invention observed at low reportedirradiances. This is also consistent with clinical experience andin-vitro studies of laser-tissue interaction, wherein increasingirradiance may simply increase the risk of thermal retinal damagewithout improving the therapeutic effect.

Another mechanism through which SDM is believed to work is theactivation of heat shock proteins (HSPs). Despite a near infinitevariety of possible cellular abnormalities, cells of all types share acommon and highly conserved mechanism of repair: heat shock proteins(HSPs). HSPs are elicited almost immediately, in seconds to minutes, byalmost any type of cell stress or injury. In the absence of lethal cellinjury, HSPs are extremely effective at repairing and returning theviable cell toward a more normal functional state. Although HSPs aretransient, generally peaking in hours and persisting for a few days,their effects may be long lasting. HSPs reduce inflammation, a commonfactor in many retinal disorders, including diabetic retinopathy (DR)and AMD.

Laser treatment induces HSP activation and, in the case of retinaltreatment, thus alters and normalizes retinal cytokine expression. Themore sudden and severe the non-lethal cellular stress (such as laserirradiation), the more rapid and robust HSP production. Thus, a burst ofrepetitive low temperature thermal spikes at a very steep rate of change(˜7° C. elevation with each 100 μs micropulse, or 70,000° C./sec)produced by each SDM exposure is especially effective in stimulatingproduction of HSPs, particularly compared to non-lethal exposure tosubthreshold treatment with continuous wave lasers, which can duplicateonly the low average tissue temperature rise.

Laser wavelengths below 532 nm produce increasingly cytotoxicphotochemical effects. At 532 nm-1300 nm, and particularly 880 nm-1000nm, SDM produces photothermal, rather than photochemical, cellularstress. Thus, SDM is able to affect the tissue, including RPE, withoutdamaging it. Consistent with HSP activation, SDM produces promptclinical effects, such as rapid and significant improvement in retinalelectrophysiology, visual acuity, contrast visual acuity and improvedmacular sensitivity measured by microperimetry, as well as long-termeffects, such as reduction of DME and involution of retinalneovascularization.

In the retina, the clinical benefits of SDM are thus produced bysub-lethal photothermal RPE HSP activation. In dysfunctional RPE cells,HSP stimulation by SDM results in normalized cytokine expression, andconsequently improved retinal structure and function. The therapeuticeffects of this “low-intensity” laser/tissue interaction are thenamplified by “high-density” laser application, recruiting all thedysfunctional RPE in the targeted area, thereby maximizing the treatmenteffect. These principles define the treatment strategy of SDM describedherein. The ability of SDM to produce therapeutic effects similar toboth drugs and photocoagulation indicates that laser-induced retinaldamage (for effects other than cautery) is unnecessary andnon-therapeutic; and, in fact, detrimental because of the loss ofretinal function and incitement of inflammation.

Because normally functioning cells are not in need of repair, HSPstimulation in normal cells would tend to have no notable clinicaleffect. The “patho-selectivity” of near infrared laser effects, such asSDM, affecting sick cells but not affecting normal ones, on various celltypes is consistent with clinical observations of SDM. This facility iskey to the suitability of SDM for early and preventative treatment ofeyes with chronic progressive disease and eyes with minimal retinalabnormality and minimal dysfunction. Finally, SDM has been reported tohave a clinically broad therapeutic range, unique among retinal lasermodalities, consistent with American National Standards Institute“Maximum Permissible Exposure” predictions. While SDM may cause directphotothermal effects such as entropic protein unfolding anddisaggregation, SDM appears optimized for clinically safe and effectivestimulation of HSP-mediated retinal repair.

As SDM does not produce laser-induced retinal damage (photocoagulation),and has no known adverse treatment effect, and has been reported to bean effective treatment in a number of retinal disorders (includingdiabetic macular edema (DME) proliferative diabetic retinopathy (PDR),macular edema due to branch retinal vein occlusion (BRVO), centralserous chorioretinopathy (CSR), reversal of drug tolerance, andprophylactic treatment of progressive degenerative retinopathies such asdry age-related macular degeneration, Stargardts' disease, conedystrophies, and retinitis pigmentosa. The safety of SDM is such that itmay be used transfoveally in eyes with 20/20 visual acuity to reduce therisk of visual loss due to early fovea-involving DME.

As noted above, while SDM stimulation of HSPs is non-specific withregard to the disease process, the result of HSP mediated repair is byits nature specific to the state of the dysfunction. HSPs tend to fixwhat is wrong, whatever that might be. Thus, the observed effectivenessof SDM in retinal conditions as widely disparate as BRVO, DME, PDR, CSR,age-related and genetic retinopathies, and drug-tolerant NAMD.Conceptually, this facility can be considered a sort of “Reset toDefault” mode of SDM action. For the wide range of disorders in whichcellular function is critical, SDM normalizes cellular function bytriggering a “reset” (to the “factory default settings”) viaHSP-mediated cellular repair.

The inventors have found that SDM treatment of patients suffering fromage-related macular degeneration (AMD) can slow the progress or evenstop the progression of AMD. Most of the patients have seen significantimprovement in dynamic functional log MAR mesoptic visual acuity andmesoptic contrast visual acuity after the SDM treatment. It is believedthat SDM works by targeting, preserving, and “normalizing” (movingtoward normal) function of the retinal pigment epithelium (RPE).

SDM has also been shown to stop or reverse the manifestations of thediabetic retinopathy disease state without treatment-associated damageor adverse effects, despite the persistence of systemic diabetesmellitus. On this basis it is hypothesized that SDM might work byinducing a return to more normal cell function and cytokine expressionin diabetes-affected RPE cells, analogous to hitting the “reset” buttonof an electronic device to restore the factory default settings. Basedon the above information and studies, SDM treatment may directly affectcytokine expression via heat shock protein (HSP) activation in thetargeted tissue.

As indicated above, subthreshold diode micropulsed laser (SDM)photostimulation has been effective in stimulating direct repair ofslightly misfolded proteins in eye tissue. Besides HSP activation,another way this may occur is because the spikes in temperature causedby the micropulses in the form of a thermal time-course allows diffusionof water inside proteins, and this allows breakage of thepeptide-peptide hydrogen bonds that prevent the protein from returningto its native state. The diffusion of water into proteins results in anincrease in the number of restraining hydrogen bonds by a factor on theorder of a thousand. Thus, it is believed that this process could beapplied to other diseases advantageously as well.

As explained above, the energy source to be applied to the target tissuewill have energy and operating parameters which must be determined andselected so as to achieve the therapeutic effect while not permanentlydamaging the tissue. Using a light beam energy source, such as a laserlight beam, as an example, the laser wavelength, duty cycle and totalpulse train duration parameters must be taken into account. Otherparameters which can be considered include the radius of the lasersource as well as the average laser power. Adjusting or selecting one ofthese parameters can have an effect on at least one other parameter.

FIGS. 1 and 2 illustrate graphs showing the average power in watts ascompared to the laser source radius (between 0.1 cm and 0.4 cm) andpulse train duration (between 0.1 and 0.6 seconds). FIG. 1 shows awavelength of 880 nm, whereas FIG. 2 has a wavelength of 1000 nm. It canbe seen in these figures that the required power decreases monotonicallyas the radius of the source decreases, as the total train durationincreases, and as the wavelength decreases. The preferred parameters forthe radius of the laser source is 1 mm-4 mm. For a wavelength of 880 nm,the minimum value of power is 0.55 watts, with a radius of the lasersource being 1 mm, and the total pulse train duration being 600milliseconds. The maximum value of power for the 880 nm wavelength is52.6 watts when the laser source radius is 4 mm and the total pulsedrain duration is 100 milliseconds. However, when selecting a laserhaving a wavelength of 1000 nm, the minimum power value is 0.77 wattswith a laser source radius of 1 mm and a total pulse train duration of600 milliseconds, and a maximum power value of 73.6 watts when the lasersource radius is 4 mm and the total pulse duration is 100 milliseconds.The corresponding peak powers, during an individual pulse, are obtainedfrom the average powers by dividing by the duty cycle.

The volume of the tissue region to be heated is determined by thewavelength, the absorption length in the relevant tissue, and by thebeam width. The total pulse duration and the average laser powerdetermine the total energy delivered to heat up the tissue, and the dutycycle of the pulse train gives the associated spike, or peak, powerassociated with the average laser power. Preferably, the pulsed energysource energy parameters are selected so that approximately 20 to 40joules of energy is absorbed by each cubic centimeter of the targettissue.

It has been determined that the target tissue can be heated to up toapproximately 11° C. for a short period of time, such as less than onesecond, to create the therapeutic effect of the invention whilemaintaining the target tissue average temperature to a lower temperaturerange, such as less than 6° C. or even 1° C. or less over a prolongedperiod of time, such as several minutes. The selection of the duty cycleand the total pulse train duration provide time intervals in which theheat can dissipate. A duty cycle of less than 10%, and preferablybetween 2.5% and 5%, with a total pulse duration of between 100milliseconds and 600 milliseconds has been found to be effective.

It has been found that the average temperature rise of the desiredtarget region increasing at least 6° C. and up to 11° C., and preferablyapproximately 10° C., during the total irradiation period results in HSPactivation. The control of the target tissue temperature is determinedby choosing source and target parameters such that the Arrheniusintegral for HSP activation is larger than 1, while at the same timeassuring compliance with the conservative FDA/FCC requirements foravoiding damage or a damage Arrhenius integral being less than 1.

In order to meet the conservative FDA/FCC constraints to avoid permanenttissue damage, for light beams, and other electromagnetic radiationsources, the average temperature rise of the target tissue over anysix-minute period is 1° C. or less. The typical decay times required forthe temperature in the heated target region to decrease by thermaldiffusion from a temperature rise of approximately 10° C. to 1° C. whenthe wavelength is 880 nm and the source diameter is 1 millimeter, thetemperature decay time is 16 seconds. The temperature decay time is 107seconds when the source diameter is 4 mm. When the wavelength is 1000nm, the temperature decay time is 18 seconds when the source diameter is1 mm and 136 seconds when the source diameter is 4 mm. This is wellwithin the time of the average temperature rise being maintained overthe course of several minutes, such as 6 minutes or less. While thetarget tissue's temperature is raised, such as to approximately 10° C.,very quickly, such as in a fraction of a second during the applicationof the energy source to the tissue, the relatively low duty cycleprovides relatively long periods of time between the pulses of energyapplied to the tissue and the relatively short pulse train durationensure sufficient temperature diffusion and decay within a relativelyshort period of time comprising several minutes, such as 6 minutes orless, that there is no permanent tissue damage.

The pulse train mode of energy delivery has a distinct advantage over asingle pulse or gradual mode of energy delivery, as far as theactivation of remedial HSPs and the facilitation of protein repair isconcerned. There are two considerations that enter into this advantage:first, a big advantage for HSP activation and protein repair in an SDMenergy delivery mode comes from producing a spike temperature of theorder of 10° C. This large rise in temperature has a big impact on theArrhenius integrals that describe quantitatively the number of HSPs thatare activated and the rate of water diffusion into the proteins thatfacilitates protein repair. This is because the temperature enters intoan exponential that has a big amplification effect. Second, it isimportant that the temperature rise not remain at the high value (10° C.or more) for long, because then it would violate the FDA and FCCrequirements that over periods of minutes the average temperature risemust be less than 1° C. (or in the case of ultrasound 6° C.).

An SDM mode of energy delivery uniquely satisfies both of theseforegoing considerations by judicious choice of the power, pulse time,pulse interval, and the volume of the target region to be treated. Thevolume of the treatment region enters because the temperature must decayfrom its high value of the order of 10° C. fairly rapidly in order forthe long term average temperature rise not to exceed the long termFDA/FCC limit of 6° C. for ultrasound frequencies and 1° C. or less forelectromagnetic radiation energy sources.

With reference now to FIG. 3, a schematic diagram is shown of a systemfor realizing the process of the present invention. The system,generally referred to by the reference number 30, includes a laserconsole 32, such as for example the 810 nm near infrared micropulseddiode laser in the preferred embodiment. The laser generates a laserlight beam which is passed through optics, such as an optical lens ormask, or a plurality of optical lenses and/or masks 34 as needed. Thelaser projector optics 34 pass the shaped light beam to a coaxialwide-field non-contact digital optical viewing system/camera 36 forprojecting the laser beam light onto the eye 38 of the patient. It willbe understood that the box labeled 36 can represent both the laser beamprojector as well as a viewing system/camera, which might in realitycomprise two different components in use. The viewing system/camera 36provides feedback to a display monitor 40, which may also include thenecessary computerized hardware, data input and controls, etc. formanipulating the laser 32, the optics 34, and/or the projection/viewingcomponents 36.

As discussed above, current treatment requires the application of alarge number of individual laser beam spots singly applied to the targettissue to be treated. These can number in the hundreds or even thousandsfor the desired treatment area. This is very time intensive andlaborious.

With reference now to FIG. 4, in one embodiment, the laser light beam 42is passed through a collimator lens 44 and then through a mask 46. In aparticularly preferred embodiment, the mask 46 comprises a diffractiongrating. The mask/diffraction grating 46 produces a geometric object, ormore typically a geometric pattern of simultaneously produced multiplelaser spots or other geometric objects. This is represented by themultiple laser light beams labeled with reference number 48.Alternatively, the multiple laser spots may be generated by a pluralityof fiber optic wires. Either method of generating laser spots allows forthe creation of a very large number of laser spots simultaneously over avery wide treatment field, such as consisting of the entire retina. Infact, a very high number of laser spots, perhaps numbering in thehundreds, even thousands or more could cover the entire ocular fundusand entire retina, including the macula and fovea, retinal blood vesselsand optic nerve. The intent of the process in the present invention isto better ensure complete and total coverage and treatment, sparing noneof the retina by the laser so as to improve vision.

Using optical features with a feature size on par with the wavelength ofthe laser employed, for example using a diffraction grating, it ispossible to take advantage of quantum mechanical effects which permitssimultaneous application of a very large number of laser spots for avery large target area. The individual spots produced by suchdiffraction gratings are all of a similar optical geometry to the inputbeam, with minimal power variation for each spot. The result is aplurality of laser spots with adequate irradiance to produce harmlessyet effective treatment application, simultaneously over a large targetarea. The present invention also contemplates the use of other geometricobjects and patterns generated by other diffractive optical elements.

The laser light passing through the mask 46 diffracts, producing aperiodic pattern a distance away from the mask 46, shown by the laserbeams labeled 48 in FIG. 4. The single laser beam 42 has thus beenformed into multiple, up to hundreds or even thousands, of individuallaser beams 48 so as to create the desired pattern of spots or othergeometric objects. These laser beams 48 may be passed through additionallenses, collimators, etc. 50 and 52 in order to convey the laser beamsand form the desired pattern on the patient's retina. Such additionallenses, collimators, etc. 50 and 52 can further transform and redirectthe laser beams 48 as needed.

Arbitrary patterns can be constructed by controlling the shape, spacingand pattern of the optical mask 46. The pattern and exposure spots canbe created and modified arbitrarily as desired according to applicationrequirements by experts in the field of optical engineering.Photolithographic techniques, especially those developed in the field ofsemiconductor manufacturing, can be used to create the simultaneousgeometric pattern of spots or other objects.

Although hundreds or even thousands of simultaneous laser spots could begenerated and created and formed into patterns to be applied to the eyetissue, due to the requirements of not overheating the eye tissue, andparticularly the eye lens, there are constraints on the number oftreatment spots or beams which can be simultaneously used in accordancewith the present invention. Each individual laser beam or spot requiresa minimum average power over a train duration to be effective. However,at the same time, eye tissue cannot exceed certain temperature riseswithout becoming damaged. For example, there is a 4° C. restriction onthe eye lens temperature rise which would set an upper limit on theaverage power that can be sent through the lens so as not to overheatand damage the lens of the eye. For example, using an 810 nm wavelengthlaser, the number of simultaneous spots generated and used could numberfrom as few as 1 and up to approximately 100 when a 0.04 (4%) duty cycleand a total train duration of 0.3 seconds (300 milliseconds) is used forpanretinal coverage. The water absorption increases as the wavelength isincreased, resulting in heating over the long path length through thevitreous humor in front of the retina. For shorter wavelengths, e.g.,577 nm, the absorption coefficient in the RPE's melanin can be higher,and therefore the laser power can be lower. For example, at 577 nm, thepower can be lowered by a factor of 4 for the invention to be effective.Accordingly, there can be as few as a single laser spot or up toapproximately 400 laser spots when using the 577 nm wavelength laserlight, while still not harming or damaging the eye.

The present invention can use a multitude of simultaneously generatedtherapeutic light beams or spots, such as numbering in the dozens oreven hundreds, as the parameters and methodology of the presentinvention create therapeutically effective yet non-destructive andnon-permanently damaging treatment, allowing the laser light spots to beapplied to any portion of the retina, including the fovea, whereasconventional techniques are not able to use a large number ofsimultaneous laser spots, and are often restricted to only one treatmentlaser beam, in order to avoid accidental exposure of sensitive areas ofthe retina, such as the fovea, as these will be damaged from theexposure to conventional laser beam methodologies, which could causeloss of eyesight and other complications.

FIG. 5 illustrates diagrammatically a system which couples multiplelight sources into the pattern-generating optical subassembly describedabove. Specifically, this system 30′ is similar to the system 30described in FIG. 3 above. The primary differences between the alternatesystem 30′ and the earlier described system 30 is the inclusion of aplurality of laser consoles 32, the outputs of which are each fed into afiber coupler 54. The fiber coupler produces a single output that ispassed into the laser projector optics 34 as described in the earliersystem. The coupling of the plurality of laser consoles 32 into a singleoptical fiber is achieved with a fiber coupler 54 as is known in theart. Other known mechanisms for combining multiple light sources areavailable and may be used to replace the fiber coupler described herein.

In this system 30′ the multiple light sources 32 follow a similar pathas described in the earlier system 30, i.e., collimated, diffracted,recollimated, and directed into the retina with a steering mechanism. Inthis alternate system 30′ the diffractive element must functiondifferently than described earlier depending upon the wavelength oflight passing through, which results in a slightly varying pattern. Thevariation is linear with the wavelength of the light source beingdiffracted. In general, the difference in the diffraction angles issmall enough that the different, overlapping patterns may be directedalong the same optical path through the steering mechanism 36 to theretina 38 for treatment. The slight difference in the diffraction angleswill affect how the steering pattern achieves coverage of the retina.

Since the resulting pattern will vary slightly for each wavelength, asequential offsetting to achieve complete coverage will be different foreach wavelength. This sequential offsetting can be accomplished in twomodes. In the first mode, all wavelengths of light are appliedsimultaneously without identical coverage. An offsetting steeringpattern to achieve complete coverage for one of the multiple wavelengthsis used. Thus, while the light of the selected wavelength achievescomplete coverage of the retina, the application of the otherwavelengths achieves either incomplete or overlapping coverage of theretina. The second mode sequentially applies each light source of avarying or different wavelength with the proper steering pattern toachieve complete coverage of the retina for that particular wavelength.This mode excludes the possibility of simultaneous treatment usingmultiple wavelengths, but allows the optical method to achieve identicalcoverage for each wavelength. This avoids either incomplete oroverlapping coverage for any of the optical wavelengths.

These modes may also be mixed and matched. For example, two wavelengthsmay be applied simultaneously with one wavelength achieving completecoverage and the other achieving incomplete or overlapping coverage,followed by a third wavelength applied sequentially and achievingcomplete coverage.

FIG. 6 illustrates diagrammatically yet another alternate embodiment ofthe inventive system 30″. This system 30″ is configured generally thesame as the system 30 depicted in FIG. 3. The main difference resides inthe inclusion of multiple pattern-generating subassembly channels tunedto a specific wavelength of the light source. Multiple laser consoles 32are arranged in parallel with each one leading directly into its ownlaser projector optics 34. The laser projector optics of each channel 58a, 58 b, 58 c comprise a collimator 44, mask or diffraction grating 48and recollimators 50, 52 as described in connection with FIG. 4above—the entire set of optics tuned for the specific wavelengthgenerated by the corresponding laser console 32. The output from eachset of optics 34 is then directed to a beam splitter 56 for combinationwith the other wavelengths. It is known by those skilled in the art thata beam splitter used in reverse can be used to combine multiple beams oflight into a single output.

The combined channel output from the final beam splitter 56 c is thendirected through the camera 36 which applies a steering mechanism toallow for complete coverage of the retina 38.

In this system 30″ the optical elements for each channel are tuned toproduce the exact specified pattern for that channel's wavelength.Consequently, when all channels are combined and properly aligned asingle steering pattern may be used to achieve complete coverage of theretina for all wavelengths.

The system 30″ may use as many channels 58 a, 58 b, 58 c, etc. and beamsplitters 56 a, 56 b, 56 c, etc. as there are wavelengths of light beingused in the treatment.

Implementation of the system 30″ may take advantage of differentsymmetries to reduce the number of alignment constraints. For example,the proposed grid patterns are periodic in two dimensions and steered intwo dimensions to achieve complete coverage. As a result, if thepatterns for each channel are identical as specified, the actual patternof each channel would not need to be aligned for the same steeringpattern to achieve complete coverage for all wavelengths. Each channelwould only need to be aligned optically to achieve an efficientcombination.

In system 30″, each channel begins with a light source 32, which couldbe from an optical fiber as in other embodiments of thepattern-generating subassembly. This light source 32 is directed to theoptical assembly 34 for collimation, diffraction, recollimation anddirected into the beam splitter which combines the channel with the mainoutput.

The field of photobiology reveals that different biologic effects may beachieved by exposing target tissues to lasers of different wavelengths.The same may also be achieved by consecutively applying multiple lasersof either different or the same wavelength in sequence with variabletime periods of separation and/or with different irradiant energies. Thepresent invention anticipates the use of multiple laser, light orradiant wavelengths (or modes) applied simultaneously or in sequence tomaximize or customize the desired treatment effects. This method alsominimizes potential detrimental effects. The optical methods and systemsillustrated and described above provide simultaneous or sequentialapplication of multiple wavelengths.

The invention described herein is generally safe for panretinal and/ortrans-foveal treatment. However, it is possible that a user, i.e.,surgeon, preparing to limit treatment to a particular area of the retinawhere disease markers are located or to prevent treatment in aparticular area with darker pigmentation, such as from scar tissue. Inthis case, the camera 36 may be fitted with an iris aperture 72configured to selectively widen or narrow the opening through which thelight is directed into the eye 38 of the patient. FIG. 7 illustrates anopening 74 on a camera 36 fitted with such an iris aperture 72.Alternatively, the iris aperture 72 may be replaced or supplemented by aliquid crystal display (LCD) 76. The LCD 76 acts as a dynamic apertureby allowing each pixel in the display to either transmit or block thelight passing through it. Such an LCD 76 is depicted in FIG. 8.

Preferably, any one of the inventive systems 30, 30′, 30″ includes adisplay on a user interface with a live image of the retina as seenthrough the camera 36. The user interface may include an overlay of thislive image of the retina to select areas where the treatment light willbe limited or excluded by the iris aperture 72 and/or the LCD 76. Theuser may draw an outline on the live image as on a touch screen and thenselect for either the inside or the outside of that outline to havelimited or excluded coverage.

By way of example, if the user identifies scar tissue on the retina thatshould be excluded from treatment, the user would draw an outline aroundthe scar tissue and then mark the interior of that outline for exclusionfrom the laser treatment. The control system and user interface wouldthen send the proper control signal to the LCD 76 to block the projectedtreatment light through the pixels over the selected scar tissue. TheLCD 76 provides an added benefit of being useful for attenuating regionsof the projected pattern. This feature may be used to limit the peakpower output of certain spots within the pattern. Limiting the peakpower of certain spots in the pattern with the highest power output canbe used to make the treatment power more uniform across the retina.

Alternatively, the surgeon may use the fundus monitor to outline an areaof the retina to be treated or avoided; and the designated area thentreated or avoided by software directing the treatment beams to treat oravoid said areas without need or use of an obstructing LCD 76 diaphragm.

Typically, the system of the present invention incorporates a guidancesystem to ensure complete and total retinal treatment with retinalphotostimulation. This guidance system is to be distinguished fromtraditional retinal laser guidance systems that are employed to bothdirect treatment to a specific retinal location; and to direct treatmentaway from sensitive locations such as the fovea that would be damaged byconventional laser treatment, as the treatment method of the presentinvention is harmless, the entire retina, including the fovea and evenoptical nerve, can be treated. Moreover, protection against accidentalvisual loss by accidental patient movement is not a concern. Instead,patient movement would mainly affect the guidance in tracking of theapplication of the laser light to ensure adequate coverage.Fixation/tracking/registration systems consisting of a fixation target,tracking mechanism, and linked to system operation are common in manyophthalmic diagnostic systems and can be incorporated into the presentinvention.

In a particularly preferred embodiment, the geometric pattern ofsimultaneous laser spots is sequentially offset so as to achieveconfluent and complete treatment of the retinal surface. Although asegment of the retina can be treated in accordance with the presentinvention, more ideally the entire retina will be treated within onetreatment session. This is done in a time-saving manner by placing aplurality of spots over the entire ocular fundus at once. This patternof simultaneous spots is scanned, shifted, or redirected as an entirearray sequentially, so as to cover the entire retina in a singletreatment session.

This can be done in a controlled manner using an optical scanningmechanism 60. FIGS. 9 and 10 illustrate an optical scanning mechanism 60which may be used in the form of a MEMS mirror, having a base 62 withelectronically actuated controllers 64 and 66 which serve to tilt andpan the mirror 68 as electricity is applied and removed thereto.Applying electricity to the controller 64 and 66 causes the mirror 68 tomove, and thus the simultaneous pattern of laser spots or othergeometric objects reflected thereon to move accordingly on the retina ofthe patient. This can be done, for example, in an automated fashionusing an electronic software program to adjust the optical scanningmechanism 60 until complete coverage of the retina, or at least theportion of the retina desired to be treated, is exposed to thephototherapy. The optical scanning mechanism may also be a small beamdiameter scanning galvo mirror system, or similar system, such as thatdistributed by Thorlabs. Such a system is capable of scanning the lasersin the desired offsetting pattern.

Since the parameters of the present invention dictate that the appliedradiant energy or laser light is not destructive or damaging, thegeometric pattern of laser spots, for example, can be overlapped withoutdestroying the tissue or creating any permanent damage. However, in aparticularly preferred embodiment, as illustrated in FIG. 11, thepattern of spots are offset at each exposure so as to create spacebetween the immediately previous exposure to allow heat dissipation andprevent the possibility of heat damage or tissue destruction. Thus, asillustrated in FIG. 11, the pattern, illustrated for exemplary purposesas a grid of sixteen spots, is offset each exposure such that the laserspots occupy a different space than previous exposures. It will beunderstood that the diagrammatic use of circles or empty dots as well asfilled dots are for diagrammatic purposes only to illustrate previousand subsequent exposures of the pattern of spots to the area, inaccordance with the present invention. The spacing of the laser spotsprevents overheating and damage to the tissue. It will be understoodthat this occurs until the entire retina, the preferred methodology, hasreceived phototherapy, or until the desired effect is attained. This canbe done, for example, by a scanning mechanism, such as by applyingelectrostatic torque to a micromachined mirror, as illustrated in FIGS.9 and 10. By combining the use of small retina laser spots separated byexposure free areas, prevents heat accumulation, and grids with a largenumber of spots per side, it is possible to atraumatically and invisiblytreat large target areas with short exposure durations far more rapidlythan is possible with current technologies.

By rapidly and sequentially repeating redirection or offsetting of theentire simultaneously applied grid array of spots or geometric objects,complete coverage of the target, such as a human retina, can be achievedrapidly without thermal tissue injury. This offsetting can be determinedalgorithmically to ensure the fastest treatment time and least risk ofdamage due to thermal tissue, depending on laser parameters and desiredapplication. The following has been modeled using the FraunhofferApproximation. With a mask having a nine by nine square lattice, with anaperture radius 9 μm, an aperture spacing of 600 μm, using a 890 nmwavelength laser, with a mask-lens separation of 75 mm, and secondarymask size of 2.5 mm by 2.5 mm, the following parameters will yield agrid having nineteen spots per side separated by 133 μm with a spot sizeradius of 6 μm. The number of exposures “m” required to treat (coverconfluently with small spot applications) given desired area side-length“A”, given output pattern spots per square side “n”, separation betweenspots “R”, spot radius “r” and desired square side length to treat area“A”, can be given by the following formula:

$m = {\frac{A}{nR}\mspace{14mu}{floor}\mspace{14mu}\left( \frac{R}{2r} \right)^{2}}$

With the foregoing setup, one can calculate the number of operations mneeded to treat different field areas of exposure. For example, a 3 mm×3mm area, which is useful for treatments, would require 98 offsettingoperations, requiring a treatment time of approximately thirty seconds.Another example would be a 3 cm×3 cm area, representing the entire humanretinal surface. For such a large treatment area, a much largersecondary mask size of 25 mm by 25 mm could be used, yielding atreatment grid of 190 spots per side separated by 133 μm with a spotsize radius of 6 μm. Since the secondary mask size was increased by thesame factor as the desired treatment area, the number of offsettingoperations of approximately 98, and thus treatment time of approximatelythirty seconds, is constant. These treatment times represent at leastten to thirty times reduction in treatment times compared to currentmethods of sequential individual laser spot applications. Field sizes of3 mm would, for example, allow treatment of the entire human macula in asingle exposure, useful for treatment of common blinding conditions suchas diabetic macular edema and age-related macular degeneration.Performing the entire 98 sequential offsettings would ensure entirecoverage of the macula.

Of course, the number and size of retinal spots produced in asimultaneous pattern array can be easily and highly varied such that thenumber of sequential offsetting operations required to completetreatment can be easily adjusted depending on the therapeuticrequirements of the given application.

Furthermore, by virtue of the small apertures employed in thediffraction grating or mask, quantum mechanical behavior may be observedwhich allows for arbitrary distribution of the laser input energy. Thiswould allow for the generation of any arbitrary geometric shapes orpatterns, such as a plurality of spots in grid pattern, lines, or anyother desired pattern. Other methods of generating geometric shapes orpatterns, such as using multiple fiber optical fibers or microlenses,could also be used in the present invention. Time savings from the useof simultaneous projection of geometric shapes or patterns permits thetreatment fields of novel size, such as the 1.2 cm{circumflex over ( )}2area to accomplish whole-retinal treatment, in a single clinical settingor treatment session.

With reference now to FIGS. 12 and 13, instead of a geometric pattern ofsmall laser spots, the present invention contemplates use of othergeometric objects or patterns. For example, a single line 70 of laserlight, formed by the continuously or by means of a series of closelyspaced spots, can be created. An offsetting optical scanning mechanismcan be used to sequentially scan the line over an area, illustrated bythe downward arrow in FIG. 12. With reference now to FIG. 13, the samegeometric object of a line 70 can be rotated, as illustrated by thearrows, so as to create a circular field of phototherapy. The potentialnegative of this approach, however, is that the central area will berepeatedly exposed, and could reach unacceptable temperatures. Thiscould be overcome, however, by increasing the time between exposures, orcreating a gap in the line such that the central area is not exposed.

Power limitations in current pulsed diode lasers require fairly longexposure duration. The longer the exposure, the more important thecenter-spot heat dissipating ability toward the unexposed tissue at themargins of the laser spot and toward the underlying choriocapillaris asin the retina. Thus, the pulsed laser light beam of an 810 nm diodelaser should have an exposure envelope duration of 500 milliseconds orless, and preferably approximately 300 milliseconds. Of course, ifmicropulsed diode lasers become more powerful, the exposure durationshould be lessened accordingly.

Aside from power limitations, another parameter of the present inventionis the duty cycle, or the frequency of the train of micropulses, or thelength of the thermal relaxation time between consecutive pulses. It hasbeen found that the use of a 10% duty cycle or higher adjusted todeliver micropulsed laser at similar irradiance at similar MPE levelssignificantly increase the risk of lethal cell injury, particularly indarker fundi. However, duty cycles of less than 10%, and preferably 5%or less demonstrate adequate thermal rise and treatment at the level ofthe MPE cell to stimulate a biological response, but remain below thelevel expected to produce lethal cell injury, even in darkly pigmentedfundi. The lower the duty cycle, however, the exposure envelope durationincreases, and in some instances can exceed 500 milliseconds.

Each micropulsed lasts a fraction of a millisecond, typically between 50microseconds to 100 microseconds in duration. Thus, for the exposureenvelope duration of 300-500 milliseconds, and at a duty cycle of lessthan 5%, there is a significant amount of wasted time betweenmicropulses to allow the thermal relaxation time between consecutivepulses. Typically, a delay of between 1 and 3 milliseconds, andpreferably approximately 2 milliseconds, of thermal relaxation time isneeded between consecutive pulses. For adequate treatment, the retinalcells are typically exposed or hit by the laser light between 50-200times, and preferably between 75-150 at each location. With the 1-3milliseconds of relaxation or interval time, the total time inaccordance with the embodiments described above to treat a given area,or more particularly the locations on the retina which are being exposedto the laser spots is between 200 milliseconds and 500 milliseconds onaverage. The thermal relaxation time is required so as not to overheatthe cells within that location or spot and so as to prevent the cellsfrom being damaged or destroyed. While time periods of 200-500milliseconds do not seem long, given the small size of the laser spotsand the need to treat a relatively large area of the retina, treatingthe entire macula or the entire retina can take a significant amount oftime, particularly from the perspective of a patient who is undergoingtreatment.

Accordingly, the present invention may utilize the interval betweenconsecutive laser light applications to the same location (typicallybetween 1 to 3 milliseconds) to apply the laser light to a secondtreatment area, or additional areas, of the retina and/or fovea that isspaced apart from the first treatment area. The laser beams are returnedto the first treatment location, or previous treatment locations, withinthe predetermined interval of time so as to provide sufficient thermalrelaxation time between consecutive pulses, yet also sufficiently treatthe cells in those locations or areas properly by sufficientlyincreasing the temperature of those cells over time by repeatedlyapplying the laser light to that location in order to achieve thedesired therapeutic benefits of the invention.

It is important to return to a previously treated location within 1-3milliseconds, and preferably approximately 2 milliseconds, to allow thearea to cool down sufficiently during that time, but also to treat itwithin the necessary window of time. For example, one cannot wait one ortwo seconds and then return to a previously treated area that has notyet received the full treatment necessary, as the treatment will not beas effective or perhaps not effective at all. However, during thatinterval of time, typically approximately 2 milliseconds, at least oneother area, and typically multiple areas, can be treated with a laserlight application as the laser light pulses are typically 50microseconds to 100 microseconds in duration. The number of additionalareas which can be treated is limited only by the micropulse durationand the ability to controllably move the laser light beams from one areato another. Currently, approximately four additional areas which aresufficiently spaced apart from one another can be treated during thethermal relaxation intervals beginning with a first treatment area.Thus, multiple areas can be treated, at least partially, during the200-500 millisecond exposure envelope for the first area. Thus, in asingle interval of time, instead of only 100 simultaneous light spotsbeing applied to a treatment area, approximately 500 light spots can beapplied during that interval of time in different treatment areas. Thiswould be the case, for example, for a laser light beam having awavelength of 810 nm. For shorter wavelengths, such as 570 nm, even agreater number of individual locations can be exposed to the laser beamsto create light spots. Thus, instead of a maximum of approximately 400simultaneous spots, approximately 2,000 spots could be covered duringthe interval between micropulsed treatments to a given area or location.

As mentioned above, typically each location has between 50-200, and moretypically between 75-150, light applications applied thereto over thecourse of the exposure envelope duration (typically 200-500milliseconds) to achieve the desired treatment. In accordance with anembodiment of the present invention, the laser light would be reappliedto previously treated areas in sequence during the relaxation timeintervals for each area or location. This would occur repeatedly until apredetermined number of laser light applications to each area to betreated have been achieved.

This is diagrammatically illustrated in FIGS. 14A-14D. FIG. 14Aillustrates with solid circles a first area having laser light appliedthereto as a first application. The laser beams are offset ormicroshifted to a second exposure area, followed by a third exposurearea and a fourth exposure area, as illustrated in FIG. 14B, until thelocations in the first exposure area need to be retreated by havinglaser light applied thereto again within the thermal relaxation timeinterval. The locations within the first exposure area would then havelaser light reapplied thereto, as illustrated in FIG. 14C. Secondary orsubsequent exposures would occur in each exposure area, as illustratedin FIG. 14D by the increasingly shaded dots or circles until the desirednumber of exposures or hits or light applications had been achieved totherapeutically treat these areas, diagrammatically illustrated by theblackened circles in exposure area 1 in FIG. 14D. When a first orprevious exposure area has been completed treated, this enables thesystem to add an additional exposure area, which process is repeateduntil the entire area of retina to be treated has been fully treated. Itshould be understood that the use of solid circles, broken line circles,partially shaded circles, and fully shaded circles are for explanatorypurposes only, as in fact the exposure of the laser light in accordancewith the present invention is invisible and non-detectable to both thehuman eye as well as known detection devices and techniques.

Adjacent exposure areas must be separated by at least a predeterminedminimum distance to avoid thermal tissue damage. Such distance is atleast 0.5 diameter away from the immediately preceding treated locationor area, and more preferably between 1-2 diameters away. Such spacingrelates to the actually treated locations in a previous exposure area.It is contemplated by the present invention that a relatively large areamay actually include multiple exposure areas therein which are offset ina different manner than that illustrated in FIG. 14. For example, theexposure areas could comprise the thin lines illustrated in FIGS. 12 and13, which would be repeatedly exposed in sequence until all of thenecessary areas were fully exposed and treated. In accordance with thepresent invention, this can comprise a limited area of the retina, theentire macula or panmacular treatment, or the entire retina, includingthe fovea. However, due to the methodology of the present invention, thetime required to treat that area of the retina to be treated or theentire retina is significantly reduced, such as by a factor of 4 or 5times, such that a single treatment session takes much less time for themedical provider and the patient need not be in discomfort for as longof a period of time.

In accordance with this embodiment of the invention of applying one ormore treatment beams to the retina at once, and moving the treatmentbeams to a series of new locations, then bringing the beams back toretreat the same location or area repeatedly has been found to alsorequire less power compared to the methodology of keeping the laserbeams in the same locations or area during the entire exposure envelopeduration. With reference to FIGS. 15-17, there is a linear relationshipbetween the pulse length and the power necessary, but there is alogarithmic relationship between the heat generated.

With reference to FIG. 15, a graph is provided wherein the x-axisrepresents the Log of the average power in watts and the y-axisrepresents the treatment time, in seconds. The lower curve is forpanmacular treatment and the upper curve is for panretinal treatment.This would be for a laser light beam having a micropulse time of 50microseconds, a period of 2 milliseconds period of time between pulses,and duration of train on a spot of 300 milliseconds. The areas of eachretinal spot are 100 microns, and the laser power for these 100 micronretinal spots is 0.74 watts. The panmacular area is 0.55 cm², requiring7,000 panmacular spots total, and the panretinal area is 3.30 cm²,requiring 42,000 laser spots for full coverage. Each RPE spot requires aminimum energy in order for its reset mechanism to be adequatelyactivated, in accordance with the present invention, namely, 38.85joules for panmacular and 233.1 joules for panretinal. As would beexpected, the shorter the treatment time, the larger the requiredaverage power. However, there is an upper limit on the allowable averagepower, which limits how short the treatment time can be.

As mentioned above, there are not only power constraints with respect tothe laser light available and used, but also the amount of power thatcan be applied to the eye without damaging eye tissue. For example,temperature rise in the lens of the eye is limited, such as between 4°C. so as not to overheat and damage the lens, such as causing cataracts.Thus, an average power of 7.52 watts could elevate the lens temperatureto approximately 4° C. This limitation in power increases the minimumtreatment time.

However, with reference to FIG. 16, the total power per pulse requiredis less in the microshift case of repeatedly and sequentially moving thelaser spots and returning to prior treated locations, so that the totalenergy delivered and the total average power during the treatment timeis the same. FIGS. 16 and 17 show how the total power depends ontreatment time. This is displayed in FIG. 16 for panmacular treatment,and in FIG. 17 for panretinal treatment. The upper, solid line or curverepresents the embodiment where there are no microshifts takingadvantage of the thermal relaxation time interval, such as described andillustrated in FIG. 11, whereas the lower dashed line represents thesituation for such microshifts, as described and illustrated in FIG. 14.FIGS. 16 and 17 show that for a given treatment time, the peak totalpower is less with microshifts than without microshifts. This means thatless power is required for a given treatment time using themicroshifting embodiment of the present invention. Alternatively, theallowable peak power can be advantageously used, reducing the overalltreatment time.

Thus, in accordance with FIGS. 15-17, a log power of 1.0 (10 watts)would require a total treatment time of 20 seconds using themicroshifting embodiment of the present invention, as described herein.It would take more than 2 minutes of time without the microshifts, andinstead leaving the micropulsed light beams in the same location or areaduring the entire treatment envelope duration. There is a minimumtreatment time according to the wattage. However, this treatment timewith microshifting is much less than without microshifting. As the laserpower required is much less with the microshifting, it is possible toincrease the power in some instances in order to reduce the treatmenttime for a given desired retinal treatment area. The product of thetreatment time and the average power is fixed for a given treatment areain order to achieve the therapeutic treatment in accordance with thepresent invention. This could be implemented, for example, by applying ahigher number of therapeutic laser light beams or spots simultaneouslyat a reduced power. Of course, since the parameters of the laser lightare selected to be therapeutically effective yet not destructive orpermanently damaging to the cells, no guidance or tracking beams arerequired, only the treatment beams as all areas of the retina, includingthe fovea, can be treated in accordance with the present invention. Infact, in a particularly preferred embodiment, the entire retina,including the fovea, is treated in accordance with the presentinvention, which is simply not possible using conventional techniques.

Due to the unique characteristics of the present invention, allowing asingle set of optimized laser parameters, which are not significantlyinfluenced by media opacity, retinal thickening, or fundus pigmentation,a simplified user interface is permitted. While the operating controlscould be presented and function in many different ways, the systempermits a very simplified user interface that might employ only twocontrol functions. That is, an “activate” button, wherein a singledepression of this button while in “standby” would actuate and initiatetreatment. A depression of this button during treatment would allow forpremature halting of the treatment, and a return to “standby” mode. Theactivity of the machine could be identified and displayed, such as by anLED adjacent to or within the button. A second controlled function couldbe a “field size” knob. A single depression of this button could programthe unit to produce, for example, a 3 mm focal or a “macular” fieldspot. A second depression of this knob could program the unit to producea 6 mm or “posterior pole” spot. A third depression of this knob couldprogram the unit to produce a “pan retinal” or approximately 160°-220°panoramic retinal spot or coverage area. Manual turning of this knobcould produce various spot field sizes therebetween. Within each fieldsize, the density and intensity of treatment would be identical.Variation of the field size would be produced by optical or mechanicalmasking or apertures, such as the iris or LCD apertures described below.

Fixation software could monitor the displayed image of the ocularfundus. Prior to initiating treatment of a fundus landmark, such as theoptic nerve, or any part or feature of either eye of the patient(assuming orthophoria), could be marked by the operator on the displayscreen. Treatment could be initiated and the software would monitor thefundus image or any other image-registered to any part of either eye ofthe patient (assuming orthophoria) to ensure adequate fixation. A breakin fixation would automatically interrupt treatment. A break in fixationcould be detected optically; or by interruption of low energy infraredbeams projected parallel to and at the outer margins of the treatmentbeam by the edge of the pupil. Treatment would automatically resumetoward completion as soon as fixation was established. At the conclusionof treatment, determined by completion of confluent delivery of thedesired laser energy to the target, the unit would automaticallyterminate exposure and default to the “on” or “standby” mode. Due tounique properties of this treatment, fixation interruption would notcause harm or risk patient injury, but only prolong the treatmentsession.

The laser could be projected via a wide field non-contact lens to theocular fundus. Customized direction of the laser fields or particulartarget or area of the ocular fundus other than the central area could beaccomplished by an operator joy stick or eccentric patient gaze. Thelaser delivery optics could be coupled coaxially to a wide fieldnon-contact digital ocular fundus viewing system. The image of theocular fundus produced could be displayed on a video monitor visible tothe laser operator. Maintenance of a clear and focused image of theocular fundus could be facilitated by a joy stick on the camera assemblymanually directed by the operator. Alternatively, addition of a targetregistration and tracking system to the camera software would result ina completely automated treatment system.

A fixation image could be coaxially displayed to the patient tofacilitate ocular alignment. This image would change in shape and size,color, intensity, blink or oscillation rate or other regular orcontinuous modification during treatment to avoid photoreceptorexhaustion, patient fatigue and facilitate good fixation.

In addition, the results or images from other retinal diagnosticmodalities, such as OCT, retinal angiography, or autofluoresencephotography, might be displayed in parallel or by superimposition on thedisplay image of the patient's fundus to guide, aid or otherwisefacilitate the treatment. This parallel or superimposition of images canfacilitate identification of disease, injury or scar tissue on theretina.

The inventors have found that treatment in accordance with the inventionof patients suffering from age-related macular degeneration (AMD) canslow the progress or even stop the progression of AMD. Further evidenceof this restorative treatment effect is the inventor's finding thattreatment can uniquely reduce the risk of vision loss in AMD due tochoroidal neovascularization by 80%. Most of the patients have seensignificant improvement in dynamic functional log MAR visual acuity andcontrast visual acuity after the treatment in accordance with theinvention, with some experiencing better vision. It is believed thatthis works by targeting, preserving, and “normalizing” (moving towardnormal) function of the retinal pigment epithelium (RPE).

Treatment in accordance with the invention has also been shown to stopor reverse the manifestations of the diabetic retinopathy disease statewithout treatment-associated damage or adverse effects, despite thepersistence of systemic diabetes mellitus. Studies published by theinventor have shown that the restorative effect of treatment canuniquely reduce the risk of progression of diabetic retinopathy by 85%.On this basis it is hypothesized that the invention might work byinducing a return to more normal cell function and cytokine expressionin diabetes-affected RPE cells, analogous to hitting the “reset” buttonof an electronic device to restore the factory default settings.

Based on the above information and studies, SDM treatment may directlyaffect cytokine expression and heat shock protein (HSP) activation inthe targeted tissue, particularly the retinal pigment epithelium (RPE)layer. Panretinal and panmacular SDM has been noted by the inventors toreduce the rate of progression of many retinal diseases, includingsevere non-proliferative and proliferative diabetic retinopathy, AMD,DME, etc. The known therapeutic treatment benefits of individuals havingthese retinal diseases, coupled with the absence of known adversetreatment effects, allows for consideration of early and preventativetreatment, liberal application and retreatment as necessary. The resettheory also suggests that the invention may have application to manydifferent types of RPE-mediated retinal disorders. In fact, the inventorhas recently shown that panmacular treatment can significantly improveretinal function and health, retinal sensitivity, and dynamic log MARvisual acuity and contrast visual acuity in dry age-related maculardegeneration, retinitis pigmentosa, cone-rod retinal degenerations, andStargardt's disease where no other treatment has previously been foundto do so.

Currently, retinal imaging and visual acuity testing guide management ofchronic, progressive retinal diseases. As tissue and/or organ structuraldamage and vision loss are late disease manifestations, treatmentinstituted at this point must be intensive, often prolonged andexpensive, and frequently fails to improve visual acuity and rarelyrestores normal vision. As the invention has been shown to be aneffective treatment for a number of retinal disorders without adversetreatment effects, and by virtue of its safety and effectiveness, it canalso be used to treat an eye to stop or delay the onset or symptoms ofretinal disorders prophylactically or as a preventative treatment forsuch retinal diseases. Any treatment that improves retinal function, andthus health, should also reduce disease or disorder severity,progression, untoward events and visual loss. By beginning treatmentearly, prior to pathologic structural change, and maintaining thetreatment benefit by regular functionally-guided re-treatment,structural degeneration and visual loss might thus be delayed if notprevented. Even modest early reductions in the rate of disease ordisorder progression may lead to significant long-term reductions andcomplications in visual loss. By mitigating the consequences of theprimary defect, the course of disease may be muted, progression slowed,and complications and visual loss reduced. This is reflected in theinventor's studies, finding that treatment reduces the risk ofprogression and visual loss in diabetic retinopathy by 85% and AMD by80%.

As SDM has been successfully used in homeotrophy or “reset to default”by normalizing the function of the RPE, retinal function andautoregulation and the biological function of the RPE, it is believedthat application of SDM can restore normal retinal physiology andautoregulation as well to slow, stop or even reverse the progression ofmyopia, and particularly pediatric myopia in the same way that it doesother chronic progressive retinopathies.

A laser light beam, that is sublethal and creates true subthresholdphotocoagulation or photostimulation of retinal tissue, is generated andat least a portion of the retinal tissue is exposed to the generatedlaser light beam without damaging the exposed retinal or foveal tissue,so as to provide preventative and protective treatment of the retinaltissue of the eye. The treated retina may comprise the fovea, foveola,retinal pigment epithelium (RPE), choroid, choroidal neovascularmembrane, subretinal fluid, macula, macular edema, parafovea, and/orperifovea. The laser light beam may be exposed to only a portion of theretina, or substantially the entire retina and fovea, or other eyetissue. This procedure is applied to tissue of the eye, such as retinaland/or foveal tissue, of an eye having myopia or a risk of havingmyopia.

While most treatment effects appear to be long-lasting, if notpermanent, clinical observations suggest that it can appear to wear offon occasion. Accordingly, the retina is periodically retreated. This maybe done according to a set schedule or when it is determined that theretina of the patient is to be retreated, such as by periodicallymonitoring visual and/or retinal function or condition of the patient.

Although several embodiments have been described in detail for purposesof illustration, various modifications may be made without departingfrom the scope and spirit of the invention. Accordingly, the inventionis not to be limited, except as by the appended claims.

What is claimed is:
 1. A process for preventing or treating myopia,comprising the steps of: providing a pulsed light beam; determining thatan eye is at a risk of developing myopia, including the step ofdetermining genetic inheritance and/or environmental myopia factorscomprising prolonged reading or electronic screen viewing, or that theeye has myopia; applying the pulsed light beam to a plurality of retinaland/or foveal tissue areas of an eye that has myopia or is at a risk ofhaving myopia, the light beam being applied to the plurality of eyetissue areas such that adjacent treated eye tissue areas are separatedby at least a predetermined distance to avoid thermal tissue damage;wherein the light beam has light beam parameters, including wavelengthor frequency, duty cycle and pulse train duration and power, selectedand is applied to the eye tissue so as to stimulate heat shock proteinactivation in the eye tissue and achieve a therapeutic or prophylacticeffect in the eye tissue while not damaging the eye tissue; and whereinthe pulsed light beam has a wavelength between 530 nm to 1300 nm, a dutycycle of less than 10%, and a pulse train duration between 0.1 and 0.6seconds.
 2. The process of claim 1, wherein the applying step includesthe step of raising the eye tissue temperature between six degreesCelsius to eleven degrees Celsius at least during application of thepulsed light beam while maintaining an average eye tissue temperatureover several minutes below a predetermined level.
 3. The process ofclaim 2, wherein the total temperature increase of the eye tissue ismaintained at approximately one degree Celsius or less over severalminutes.
 4. The process of claim 3, wherein the total temperatureincrease of the eye tissue is maintained at one degree Celsius or lessover a six minute period of time.
 5. The process of claim 1, wherein thepulsed light beam is applied to a first eye tissue area and, after apredetermined period of time within a single treatment session, thepulsed light beam is reapplied to the first eye tissue area, and duringan interval between pulsed light beam applications to the first eyetissue area the pulsed light beam is applied to a second eye tissuearea.
 6. The process of claim 1, wherein the pulsed light beam has aduty cycle between 2.5% and 5%, a wavelength between 880 nm and 1000 nm.7. The process of claim 6, wherein the pulsed light beam has a powerbetween 0.5 and 74 watts.
 8. The process of claim 1, wherein a pluralityof pulsed light beam treatment beams are simultaneously applied to theretinal tissue.
 9. The process of claim 1, wherein the pulsed light beamis applied to substantially the entire retina, including the fovea, ofthe eye.
 10. The process of claim 5, wherein the pulsed light beam isapplied to the second eye tissue area between pulses applied to thefirst tissue area, and the pulsed light beam is returned and reappliedto the first eye tissue area in less than one second.
 11. A process forpreventing or treating myopia, comprising the steps of: providing apulsed light beam source having light beam parameters includingwavelength or frequency, duty cycle and pulse train duration, the lightbeam parameters selected so as to achieve a therapeutic or prophylacticeffect while not damaging eye tissue; determining that an eye is at arisk of having myopia, including the step of determining geneticinheritance and/or environmental myopia factors comprising prolongedreading or electronic screen viewing, or that the eye has myopia; andapplying the pulsed light beam to retinal tissue, including at least aportion of the fovea, of the eye determined to have myopia or a risk ofhaving myopia to stimulate heat shock protein activation in the eyetissue; wherein the pulsed light beam has a wavelength between 530 nm to1300 nm, a duty cycle of less than 10%, and a pulse train durationbetween 0.1 and 0.6 seconds.
 12. The process of claim 11, wherein thepulsed light beam has a duty cycle between 2.5% and 5%, a wavelengthbetween 880 nm and 1000 nm.
 13. The process of claim 12, wherein thepulsed light beam has a power between 0.5 and 74 watts.
 14. The processof claim 11, wherein the pulsed light beam is applied to a first eyetissue area and, after a predetermined period of time within a singletreatment session, the pulsed light beam is reapplied to the first eyetissue area, and during an interval between pulsed light beamapplications to the first eye tissue area the pulsed light beam isapplied to a second eye tissue area.
 15. The process of claim 11,wherein the pulsed light beam is applied to a plurality of eye tissueareas, and wherein adjacent pulsed light beam treated eye tissue areasare separated by at least a predetermined distance to avoid thermaltissue damage.
 16. The process of claim 11, wherein the applying stepincludes the step of raising the eye tissue temperature between sixdegrees Celsius to eleven degrees Celsius at least during application ofthe pulsed light beam while maintaining an average eye tissuetemperature over several minutes below a predetermined level.
 17. Theprocess of claim 16, wherein the total temperature increase of the eyetissue is maintained at approximately one degree Celsius or less overseveral minutes.
 18. The process of claim 17, wherein the totaltemperature increase of the eye tissue is maintained at one degreeCelsius or less over a six minute period of time.
 19. The process ofclaim 11, wherein the pulsed light beam is applied to substantially theentire retina, including the fovea, of the eye.
 20. The process of claim11, wherein a plurality of pulsed light beam treatment beams aresimultaneously applied to the retinal tissue.
 21. The process of claim11 wherein the pulsed light beam is applied to a first eye tissue areaand, between pulses of the pulsed light beam to the first eye tissuearea the pulsed light beam is applied to a second eye tissue area spacedapart from the first eye tissue area, and after a predetermined periodof time of less than one second, the pulsed light beam is returned andreapplied to the first eye tissue area.
 22. A process for preventing ortreating myopia, comprising the steps of: providing a pulsed light beamhaving light beam parameters including wavelength or frequency, dutycycle and pulse train duration, the light beam parameters selected so asto achieve a therapeutic or prophylactic effect while not permanentlydamaging eye tissue; determining that an eye has a risk of myopia due togenetic inheritance or elevated time reading or viewing electronicscreens, or that the eye has myopia; and applying the pulsed light beamto retinal and/or foveal tissue of the eye determined to have myopia ora risk of having myopia to stimulate heat shock protein activation inthe eye tissue; wherein the pulsed light beam is applied to a pluralityof eye tissue areas, and wherein adjacent pulsed light beam treated eyetissue areas are separated by at least a predetermined distance to avoidthermal tissue damage; and wherein the pulsed light beam comprises apulsed light beam having a wavelength between 530 nm to 1300 nm, a dutycycle of less than 10%, and a pulse train duration between 0.1 and 0.6seconds.
 23. The process of claim 22, wherein the applying step includesthe step of raising the eye tissue temperature between six degreesCelsius to eleven degrees Celsius at least during application of thepulsed light beam source while maintaining an average eye tissuetemperature over several minutes below a predetermined level.
 24. Theprocess of claim 23, wherein the total temperature increase of the eyetissue is maintained at one degree Celsius or less over a six minuteperiod of time.
 25. The process of claim 22, wherein the pulsed lightbeam is applied to a first eye tissue area and, after a predeterminedperiod of time within a single treatment session, the pulsed light beamis reapplied to the first eye tissue area, and during an intervalbetween pulsed light beam applications to the first eye tissue areacomprising less than one second the pulsed light beam is applied to asecond eye tissue area.
 26. The process of claim 22, wherein the pulsedlight beam has a duty cycle between 2.5% and 5%, a wavelength between880 nm and 1000 nm.
 27. The process of claim 26, wherein the pulsedlight beam has a power between 0.5 and 74 watts.
 28. The process ofclaim 22, wherein a plurality of pulsed treatment light beams aresimultaneously applied to the retinal tissue.
 29. The process of claim22, wherein the pulsed light beam is applied to substantially the entireretina, including the fovea, of the eye.